KR19990008354A - Ester of carbapenem - Google Patents

Abstract

The compounds of formula (I) of the present invention are useful for treating bacterial infections:

(I)

(A)

(B)

In the above formula, R is (a), wherein R ^? Is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl; R ^{< beta >} is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl; R ^α and R ^β is optionally substituted with or without an additional heteroatom, or to form an unsubstituted 5 or 6 membered heterocyclic ring together; R ¹ is fluorine, a hydroxy group that is not protected or protected by an easily removable hydroxy protecting group, or a (C _1-6 ) alkyl (C _1-6 ) alkyl group that is unsubstituted or substituted by an amino group that is not protected or protected by an easily removable amino protecting group ego; R ² is hydrogen or methyl; R ³ is R ₁ is hydrogen or (C _1-6), R ₂ is hydrogen, substituted by halogen or unsubstituted (C _1-6) alkyl, (C _1-6) alkenyl, (C _1-6 ) alkoxycarbonyl, aryl or heteroaryl, R ₃ is hydrogen, (C _1-6) alkyl or (C _1-6) alkoxycarbonyl, and the formula (i R ₄ is an ester forming group, a pharmaceutically acceptable ) group (a), and R ^a is hydrogen, (C _1-6) alkyl, (C _3-7) cycloalkyl, methyl, or phenyl, R ^b is (C _1-6) alkyl (C _3-7 of ) are selected from cycloalkyloxy or (C _1-6) alkoxy (C _1-6) alkyl group of the formula (b), that is, the group consisting of CH (R ^a) OCOR ^b.

Description

Ester of carbapenem

Carbapenems such as imipenem, a compound of formula (A), have efficaciously broad antibacterial activity (see, for example, U.S. Patent No. 3,950,357 and U.S. Patent No. 4,194,047, Merck & Co.,

(A)

However, the carbapenems have a tendency to be vulnerable to hydrolysis by dehydroepeptidase-1 (DHP-1) of the enzyme, the kidney, and this tendency limits their use in chemotherapy. In the case of imipenem, this problem can be overcome by co-administration of an inhibitor of DHP-1.

The stability to DHP-1 can also be provided by chemically altering the carbapenem nucleus, for example by incorporating a 1 [beta] -methyl substituent, as in the compound of formula (B) meropenem [Reference: Shih DH et al., J. Heterocycles, 1984, 21 , 29 and Sunagawa M. et al., J. Antibiotics, 1990, 43 , 519]

(B)

Most recently, this incorporation method has evolved into 1 [beta] -aminoalkyl substituents (see, for example, European Patent No. 0 433 759 in which the applicant is Bristol-Meyers Squibb).

In another study to improve stability against DHP-1, 2-carbon substituted carbapenems such as 2-aryl, 2-heteroaryl and 2-heteroaromatic carbapenems (see US 4 543 257, US 4 260 627, US 4 962 101, US 4 978 659, EP 0 14 493, EP 0 414 489, EP 0 010 316 and EP 0 030 032 Merck Co), and 2- (substituted) Bafenem [Reference: Schmidt et al, J. Antibiotics, 41 , 1988, 780] is used. British Patent No. 1 593 524, the applicant's Merck & Company, describes a number of 5-membered heteroaromatic carbapenem derivatives comprising diazonyl and tetrazolyl compounds. However, in the case of a pyrazolyl derivative, a heterocyclic compound is attached to the carbapenem nucleus through the C-4 position.

Other structural changes introduced in position-2 include, for example, when R _a is hydrogen or methyl and R _b is hydrogen or lower alkyl (see, e. G., European Patent No. 0 330, filed by Fujisawa, Or R _a and R _b are hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl (see, for example, Banyu Pharmaceutical Co., substituted vinyl groups selected from EP 0 430 037 call) and -C (R _a) = CHR _b include. However, in the absence of the 1 [beta] -methyl substituent, this change does not appear to provide stability to DHP-1.

International patent application PCT / GB94 / 02347 describes compounds of formula (C)

(C)

Wherein R is Is:

R ^? Is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl;

R ^{< beta >} is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl;

And R ^{< a} &^gt; together form a substituted or unsubstituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;

R ^c is fluorine, a hydroxy group that is either protected or not protected by a readily removable hydroxy protecting group, or a (C _1-6 ) alkyl, substituted or unsubstituted with an amino group that is not protected or protected by an easily removable amino protecting group ego;

R ^d is hydrogen or methyl;

-CO ₂ R ^e is a carboxy or carboxylate anion, or R ^e is a readily removable carboxy protecting group.

The present invention relates to antimicrobial compounds, in particular carbapenems, and processes for their preparation, as well as pharmaceutical and veterinary compositions comprising said compounds and their intermediates, and their use in antibacterial therapy.

The present invention provides compounds of formula (I)

Wherein R is Is:

R ^? Is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl;

R ^{< beta >} is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl;

R ^α and R ^β is optionally substituted with or without an additional heteroatom, or to form an unsubstituted 5 or 6 membered heterocyclic ring together;

R ¹ is fluorine, a hydroxy group that is not protected or protected by an easily removable hydroxy protecting group, or a (C _1-6 ) alkyl (C _1-6 ) alkyl group that is unsubstituted or substituted by an amino group that is not protected or protected by an easily removable amino protecting group ego;

R ² is hydrogen or methyl;

R ³ is selected from the group consisting of a group of the formula (a) and a group of the formula (b), namely CH (R ^a ) O CO R ^b :

(A)

In the above formulas (a) and (b), R ₁ is hydrogen or (C _1-6 ) alkyl,

R ₂ is hydrogen, (C _1-6 ) alkyl, (C _1-6 ) alkenyl, (C _1-6 ) alkoxycarbonyl, aryl, or heteroaryl, optionally substituted with halogen,

R ₃ is hydrogen, (C _1-6 ) alkyl, or (C _1-6 ) alkoxycarbonyl,

R < ₄ > is a pharmaceutically acceptable ester forming group,

R ^a is hydrogen, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, methyl, or phenyl,

R ^b is (C _1-6 ) alkyl (C _3-7 ) cycloalkyloxy or (C _1-6 ) alkoxy (C _1-6 ) alkyl.

The compounds of formula (I) have broad antibacterial activity and exhibit excellent stability against DHP-1.

The (C _1-6 ) alkyl group suitable for R ^α and R ^β includes straight and branched chain alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl and iso-propyl, preferably ethyl and methyl do.

Representative examples of R < ^alpha > and (R < ^beta > as (C _1-6 ) alkyl are the cases where both are methyl or ethyl. Especially preferred examples are those wherein R ^? Is ethyl and R ^? Is methyl.

Any substituents suitable for the (C _1-6 ) alkyl group as R ^α and R ^β include, for example, halogen, hydroxy, (C _1-6 ) alkoxy, carboxy and salts thereof, (C _1-6 ) alkoxycarbonyl, carbamoyl, mono- or di (C _1-6) alkyl carbamoyl, sulfamoyl, mono- and di ((C _1-6) alkyl sulfamoyl, amino, mono- and di (C _1-6) alkyl Amino, (C _1-6 ) acylamino, ureido, (C _1-6 ) alkoxycarbonylamino, aminocarbonyloxy and mono- and di (C _1-6 ) alkylaminocarbonyloxy, (C _1-6 ) alkanesulfonylamino, aryl, heterocyclyl, oxo, acyl, heteroaryl, (C _1-6 ) alkylthio, arylthio, heterocyclythio, , Arylsulfinyl, (C _1-6 ) alkanesulfonyl, arylsulfonyl, (C _1-6 ) alkoxyimino, hydroxyimino, hydrazano, benzohydroxymoyl, and 2-thiophene carbohydroxy Preferred substituents include carbamoyl, < RTI ID = 0.0 > Aryl, especially phenyl, and heteroaryl.

Preferably, the (C _1-6 ) alkyl group for R ¹ suitably has a hydroxy, fluorine or amino substituent present at site-1 of the alkyl group. Advantageously, R ¹ is ( R ) -1-hydroxyethyl.

Suitably, R ² is hydrogen.

The term aryl, as used herein, includes phenyl and naphthyl.

Suitably, the aryl group containing phenyl and naphthyl may be unsubstituted or substituted by 5 substituents, preferably 3 substituents.

A representative example where R ^? Or R ^? Is an aryl group is phenyl.

Suitable optional substituents for aryl are halogen, (C _1-6) alkyl, aryl (C _1-4) alkyl, (C _1-6) alkoxy, (C _1-6) alkoxy (C _1-6) alkyl, halo (C _1-6) alkyl, hydroxy, amino, mono- and di -N- (C _1-6) alkylamino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di- N- (C _1-6) alkyl carbamoyl, (C _1-6) alkoxycarbonyl, (C _1-6) alkoxy carboxylate, aryloxycarbonyl, (C _1-6) alkoxycarbonyl ( C _1-6) alkyl, aryl, oxy groups, ureido, guanidino, sulfonyl, amino, aminosulfonyl, (C _1-6) alkylthio, (C _1-6) alkyl, sulfinyl (C _1-6 ) Alkylsulfonyl, heterocyclyl and heterocyclyl (C _1-4 ) alkyl. In addition, the carbon atoms of two adjacent rings may be bonded by a (C _3-5 ) alkylene chain to form a carbon ring.

As used herein, the term heteroatom includes one or more oxygen, nitrogen and sulfur elements.

The term heteroaryl, as used herein, includes fused rings containing up to 4 heteroatoms in each ring, which may be substituted or unsubstituted by one aromatic and, for example, less than three substituents, Is selected from oxygen, nitrogen and sulfur. Each heteroaryl ring suitably has 5 or 6 ring atoms. The molten heteroaryl ring contains a carbon ring and must contain only one heteroaryl ring.

As used herein, the term heterocyclic and heterocyclic forms suitably include both aromatic and non-aromatic rings in a single and fused form, suitably containing up to 4 heteroatoms in each ring, unless otherwise defined. And each heteroatom is selected from oxygen, nitrogen and sulfur, and wherein the ring may be unsubstituted or substituted by, for example, up to three substituents. Each heterocycle preferably has 4 to 7, preferably 5 or 6 ring atoms. The fused heterocyclic ring system may include a carbon ring, but it must contain only one hetero ring.

Preferably, the substituents which can substitute for a heteroaryl or a heterocyclyl group include halogen, (C _1-6) alkyl, aryl (C _1-4) alkyl (C _1-6) alkoxy, (C _1-6) (C _1-6 ) alkyl, halo (C _1-6 ) alkyl, hydroxy, amino, mono- and di-N- (C _1-6 ) alkylamino, acylamino, carboxy salt, carboxyester, together, mono- and di -N- (C _1-6) alkylcarbonyl, (C _1-6) alkoxy carboxylate, aryloxycarbonyl, (C _1-6) alkoxycarbonyl (C _1-6) alkyl, aryl, oxy groups, ureido, guanidino, sulfonyl, amino, aminosulfonyl, (C _1-6) alkylthio, (C _1-6) alkylsulfinyl, (C _1-6) alkylsulfonyl , Heterocyclyl and heterocyclyl (C _1-4 ) alkyl.

Suitably, the hydroxy and amino protecting groups used in R < ¹ > are well known in the art and they can be removed under normal conditions without degrading the remaining molecules. For example, in the Protective Groups in Organic Chemistry, TW Greene, Wiley-Interscience, New York, 2nd edition, 1991, a method for protecting the hydroxy and amino groups and a method for decomposing the resulting protected derivatives And is described more easily. Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as trialkylsilyl, and also groups such as alkyloxycarbonyl, trichloroethyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitro And organoxy-carbonyls such as benzyloxycarbonyl. Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

Since the carbapenem compound of the present invention is intended to be used in the form of a pharmaceutical composition, the compound may be in a substantially pure form, for example, at least 50% pure form, more suitably at least 75% pure form (% Based on weight) should be provided. The impurity compounds can be used to prepare pharmaceutical compositions in a more pure form.

When some of the compounds of the present invention are crystallized or recrystallized from an organic solvent, the crystallization solvent may be present in the form of a crystal product. The present invention includes such solvent compounds in this range. Similarly, some of the compounds of the present invention may be crystallized or recrystallized from a solvent containing water. In such cases, the hydrated water may be present in the form of a crystalline product. The present invention includes stoichiometric hydroxides within the scope of the present invention.

The carbapenem antimicrobial compound according to the present invention may be formulated for administration in any convenient manner for use as a human or veterinary medicine according to techniques and methods known in the art with reference to other antibiotics Thus, the present invention encompasses pharmaceutical compositions comprising the antimicrobial compounds according to the invention, together with a pharmaceutically acceptable carrier or excipient, within this range. The compositions are particularly preferred for oral administration, but may be formulated for administration via any suitable route, such as oral, parenteral or topical application. The compositions may be in the form of tablets, capsules, powders, granules, tablets (lozenges), creams, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be representative unit dosages and may contain a binder such as, for example, syrup acacia, gelatin, sorbitol, tragacanth gum, or polyvinylpyrrolidone; Fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; A tableting lubricant, for example, magnesium stearate, talc, polyethylene glycol or silica; Disintegrants, for example, conventional excipients such as tomato starch; Or an acceptable wetting agent such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the ordinary pharmaceutical arts. Oral administration solutions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable excipients prior to use . The liquid preparation may contain conventional additives such as suspending agents, for example, sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan monooleate, or acacia; Non-aqueous vehicles (which may include edible oils), such as, for example, almond oil, oily esters, glycerin, polyethylene glycol, or ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And, if desired, conventional flavoring or coloring agents. Suppositories will contain conventional suppository bases such as cocoa butter or other glycerides.

For parenteral administration, fluid unit dose formulations are prepared using the compound and a sterile excipient, wherein water is preferred. Depending on the excipient and concentration used, the compound may be suspended or dissolved in an excipient. In preparing the liquid formulation, the compound may be dissolved in water for injection and in a suitable glass bottle or ampoule and in a sterilized filter before being sealed. Advantageously, drugs, preservatives and buffers, such as a local anesthetic, can be dissolved in the excipient. In order to improve the stability, the composition may be frozen after being filled with a glass bottle and the water removed under vacuum. Then, the lyophilized powder is sealed in a glass bottle, and a glass bottle containing water for injection may be supplied subsequently to reconstitute the liquid prior to use. A parenteral suspension can be prepared in substantially the same manner except that the compound is suspended in an excipient instead of dissolving it and that sterilization can not be achieved by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. Advantageously, the inclusion of a surfactant or wetting agent in the composition promotes a uniform distribution of the compound.

The composition may contain from 0.1% by weight to 99.5% by weight, preferably from 10 to 60% by weight, of the active substance, depending on the method of administration. When the composition comprises an administration unit, each unit will preferably contain from 50 to 500 mg of active ingredient. When used in adult therapy, the dosage will preferably be from 100 mg to 12 g per day, for example 1500 mg per day, for an adult patient (body weight 70 kg), depending on the route and frequency of administration. The dose amounts to about 1.5 to 170 mg / kg per day. Suitably, the dosage is 1 to 6 g per day.

The daily dosage is suitably provided by administering the compound of the present invention several times for 24 hours. Indeed, although the dose and frequency of administration most appropriate for each patient will depend on age, weight, and patient response, the physician will choose when to choose a high or low dose and a different frequency of administration, but typically 250 mg It is administered four times a day. The dose is within the scope of the present invention.

No toxicological effects are exhibited when the compounds of the present invention are administered within the above-mentioned dosage ranges.

The invention also encompasses a method of treating a bacterial infection in humans and animals, the method comprising administering a therapeutically effective amount of an antimicrobial compound of the invention.

In another aspect, the present invention also provides a method of using a compound of formula (I) for the manufacture of a medicament for treating a bacterial infection.

The compounds of the present invention are active against a wide range of gram positive and gram negative bacteria and can be used to treat a wide range of bacterial infections, including infection of patients with impaired immune system.

Among many other uses, the compounds of the present invention are valuable in treating human skin, soft tissue, respiratory tract and infectious diseases and can be used to treat mastitis in cattle.

A particular advantage of the antimicrobial active compound of the present invention is that it is stable to the? -Lactamase enzyme and is effective for the? -Lactamase-producing microorganism.

The present invention provides a process for the preparation of a compound of formula (I) wherein said process comprises reacting a corresponding compound of formula (I), wherein R is an alkali metal cation, with a compound of formula (i) or (ii) Includes:

(I)

(Ii)

XCH (R < ^a & gt ^; ) OCOR ^b

Wherein X is a leaving group such as halogen, more particularly bromine or iodine.

The reaction is typically carried out in an inert organic solvent, such as N-methylpyrrolidin-2-one, in an inert atmosphere, such as argon, at 0 to 60 ° C, for example at ambient temperature. Other suitable solvent systems include N, N'-dimethylformamide and N, N'-dimethylacetamide.

The compound of formula (i) can be prepared according to the method described in F. Ameer et al, J. Chem. Soc., (1983), 2293.

Compounds of the formula: ICH (R ^a ) O.CO.R ^b can be prepared from the corresponding chlorides by the well-known Finkelstein reaction in the art.

Compounds of the formula: ClCH (R ^a ) O.CO.R ^b can be prepared by esterifying a compound of formula R ^b COOH with chloromethyl chlorosulfate (see Binderup et al., Synthetic Commun., 14 (9), 857-864 (1984)] can be prepared by treating a compound of the formula ClCH (R ^a ) OCOCl with a compound of the formula: HR ^b in dichloromethane / pyridine (Yoshimura et al., J. Antibiot , ≪ / RTI > 1987, 40 (1), 81-90).

Compounds of formula (I) wherein R is an alkali metal cation such as sodium are described in International Patent Application No. PCT / GB94 / 02347 and hereafter Process 1.

A further method of preparing a compound of formula (I) comprises subjecting a compound of formula (II) to a carbapenem ring forming condition, followed by removal of all protecting group (s) if necessary; Converting a first group R ¹ comprising a hydroxyl substituent group into an additional group R ¹ ; Amino or fluoro group; Converting the product to a salt; And the step of esterifying the product as described above:

In this formula,

R, R ¹ and R ² are the same as defined above,

R < ³ > is an easily removable carboxy protecting group,

R ⁴ , R ⁵ and R ⁶ are the same or different and each is a substituted or unsubstituted (C _1-6 ) alkyl or a substituted or unsubstituted aryl group, preferably an n-butyl or a phenyl group.

Suitable carbapenem ring forming conditions are well known in the art.

When X is oxygen, suitable ring forming conditions include treating the compound of formula (II) with a trivalent organic phosphorus compound of formula (III): < EMI ID =

PR ⁷ (OR ⁸ ) (OR ⁹ )

In this formula,

R ⁷ is phenyl, which is unsubstituted or substituted by (C _1-4 ) alkyl, (C _1-3 ) alkoxy or (C _1-3 ) alkyl;

R ⁸ and R ⁹ may be the same or different and are each phenyl which is substituted or unsubstituted with (C _1-4 ) alkyl, allyl, benzyl or (C _1-3 ) alkyl or (C _1-3 ) alkoxy; In analogy, the method is described in European Patent Application No. 0 476 649-A, the applicant is Hoechst AG. Suitable reagents of formula (III) include trimethyl phosphite, triethyl phosphite, dimethyl methyl phosphonite and diethyl methyl phosphonite. Suitably, the reaction is carried out in an organic solvent such as tetrahydrofuran, ethyl acetate or an aromatic solvent such as benzene, toluene, xylene or mesitylene, or a halogenated hydrocarbon such as dichloromethane, trichloromethane or 1,1,2-trichloroethane Solvent, and a temperature of from 50 to 180 캜, preferably from 70 to 165 캜.

When X is the group PR < ⁴ > R < ⁵ > R < ⁶ >, the compound of formula (I) may be obtained by a Wittig cyclization reaction well known to carbapenems [Guthikonda et al, J. Med. Chem., 1987, 30 , 871]. For example, when R ⁴ , R ⁵ and R ⁶ are each phenyl, the process involves ring-closing removal of the element of triphenylphosphine oxide. Closure of the ring is preferably carried out in an inert solvent such as benzene, toluene or xylene, preferably under dry conditions and under inert atmospheric conditions and in the presence of a radical scavenger such as hydroquinone, preferably at 40 to 145 DEG C, more preferably at 80 to 140 DEG C (II, X = PR < ⁴ > R < ⁵ > R < ⁶ >). When R ⁴ , R ⁵ and R ⁶ are each n-butyl, the cyclisation reaction is carried out at a low temperature, for example, 50 ° C, as in the method described in WO 92/01695 by the Applicant, Beecham Group Lt; 0 > C or more.

In substituent R < ¹ &^gt;, the hydroxyl or amino group, if present, may optionally be protected. Suitable hydroxy protecting groups include, but are not limited to, organosilyl, for example, a trialkylsilyl group such as trimethylsilyl or t-butyldimethylsilyl, or a trialkylsilyl group such as trichloroethyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- methoxybenzyloxy Carbonyl and allyloxycarbonyl. Suitable amino protecting groups include allyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

Compounds suitable protecting group R ³ is allyl, include 4-methoxybenzyl and 4-nitrobenzyl. Of course, the conditions necessary to remove the protecting group depend on the precise nature of the protecting group. For example, when R ³ is 4-methoxybenzyl, aluminum trichloride and anisole in dichloromethane can be used at -30 ° C to -70 ° C, and R ³ can be allyl (prop-2-en- for 1-1) include triphenylphosphine, acetate / sodium 2-ethylhexanoate and tetrakis of MDC - may be used a combination of tetrakis (triphenylphosphine) palladium (0), R ³ is p -Nitrobenzyl, a hydrogenation reaction can be used on a carbon catalyst in an aqueous solvent, for example 1,4-dioxane THF ethanol, in the presence of palladium.

Compounds of formula (II) wherein X is oxygen can be prepared by reacting a compound of formula (IV) with a compound of formula (V) under acylation conditions as described in Tetrahedron Letters, 25 , 1984, 2395 Lt; RTI ID = 0.0 > of: < / RTI >

Wherein R, R ¹ and R ² are as defined above;

ClCOCO ₂ R ³

Wherein R < ³ > is a readily removable carboxy protecting group.

Compounds of formula (II) wherein X is the group PR ⁴ R ⁵ R ⁶ can be obtained from compounds of formula (IV) as defined previously by the following steps:

(a) reacting with a functional equivalent thereof, such as a suitably protected glyoxylic acid derivative or hydrate of formula (VI) under dehydrating conditions, e. g., azeotropic removal of water;

(OHC) CO ₂ R ³

Wherein R < ³ > is a readily removable carboxy protecting group.

(b) treating the intermediate formed in step (a) with a halogenating agent, such as thionyl chloride, in the presence of a suitable base such as 2,6-lutidine; And

(c) treating the intermediate formed in step (b) with a phosphorus reagent of formula (VII) in the presence of a suitable base such as 2,6-lutidine,

PR ⁴ R ⁵ R ⁶

Wherein R ⁴ , R ⁵ and R ⁶ are the same as defined above.

Compounds of formula (IV) are described in Tetrahedron Lett., 1987, 28, 507, and Can. (VIII) with a compound of formula (IX) in the presence of a base such as, for example, lithium hexamethyldisilazide (LHMDS) according to the method described in J. Chem. 1988, 66 , 1537 Can be manufactured:

Wherein R and R < ² > are the same as defined above;

R ¹ is the same as defined above, and R ¹¹ is an acyl group, for example, acetyl.

Compounds of formula (IV) can be prepared from compounds of formula (VIIIa) in the presence of a Lewis acid such as zinc chloride or trimethylsilyl trifluoromethanesulfonate in an inert organic solvent such as a halogenated hydrocarbon solvent, e.g. in dichloromethane, Can be prepared by treating a compound of formula (IXa) with a compound of formula

Wherein R and R ² are as defined above, and SiR ₃ ¹⁴ is trialkylsilyl such as trimethylsilyl or t-butyldimethylsilyl;

Wherein R ¹ and R ¹¹ are as defined above and R ¹³ is hydrogen or an amino protecting group such as a trialkylsilyl group such as trimethylsilyl. Compounds of formula (VIIIa) may be prepared by treatment of formula (VIII) with trialkylsilyl chloride or trialkylsilyl triflate, and triethylamine in MDC.

If needed the amino protecting group R ¹³ is the subsequent removal of the general formula (IXa), which R ¹³ is trimethylsilyl a mild acid treatment in the case, for example, conventional means, such as methanol and hydrochloric acid or pyridinium p- toluenesulfonate Lt; / RTI >

Compounds of formula (VIII) are well known to those skilled in the art and can be obtained by standard synthetic methods as described in the following examples.

Compounds of formula (IX) are well known to those skilled in the art and are described, for example, in Het., 1982, 17, 201 (IX, wherein R ¹ is hydroxyethyl) and EP 0 234 484 Lt; ^{1 >} is 1-fluoroethyl).

R ¹ a compound of formula (I) is amino-substituted alkyl or cycloalkyl is equivalent of the formula (I) that R ¹ contains a hydroxy group according to the procedure described in the literature [J Chem Soc, Perkin I, 1982, 3011] By the azide substitution reaction of the Mitsunobu-type of the hydroxyl group of these compounds, and can then be catalytically reduced.

Compounds of formula (I) can be prepared by reacting a compound of formula (X) with a compound of formula (XI) in a crosslinking reaction in the presence of a crosslinking reaction catalyst selected according to M, and, if necessary, And / or converting the product to a salt and / or esterifying the product as described above.

Wherein R ¹ and R ² are as defined above, R ³ is a readily removable carboxy protecting group, X ¹ is a leaving group;

M-R

Wherein M is a metal group and R is the same as defined above.

Suitable compounds of the protecting group R ³ is a 4-methoxybenzyl 4-nitrobenzyl.

Examples of suitable leaving groups X ¹ are, for example, trifluoromethanesulfonyloxy, methanesulfonyloxy, 4-toluenesulfonyloxy, fluorosulfonyloxy, chloro, bromo, iodo and diphenoxyphosphoryl Oxy.

Suitable metals for the metallo group M are well known in the art and include tin, aluminum, zinc, boron, mercury and zirconium.

Preferred examples of the metal M is a metal, for example, R ^14, R ¹⁵ and R ¹⁶ may be the same or different and each R ^14, which may be (C _1-6) alkyl, ^{R 15 R 16 Sn, B (} OR ) ₂ and ZnCl. Preferably, the metallo metal M is an organic alkyl tin R ¹⁴ R ¹⁵ R ¹⁶ Sn, and R ¹⁴ = R ¹⁵ = R ¹⁶ = methyl or n-butyl.

Suitable crosslinking catalysts are well known in the art and include palladium compounds such as the compounds described in Palladium Reagents in Organic Synthesis, RF Heck, Academic Press Ltd, 1985, especially palladium (0) and palladium (II) ≪ / RTI > Examples are tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), transdimethylbis (triphenylphosphine) palladium (II), and palladium (II) acetate , Benzylbis (triphenylphosphine) palladium (II) chloride, bis (triphenylphosphine) palladium (II) dichloride. The palladium reagent may be combined with a halide source such as zinc chloride or lithium chloride and optionally with a compound such as a phosphine ligand of palladium, for example triarylphosphine, for example tris (4-methoxyphenyl) phosphine or Tris (2,4,6-trimethoxyphenyl) phosphine; It is preferred to use it in the presence of triheteroarylphosphine, for example, tripurylphosphine, or triarylarsine, such as triphenylarsine.

When M is an organoalkyl tin R ¹⁴ R ¹⁵ R ¹⁶ Sn-, the preferred catalyst system is tris (dibenzylideneacetone) dipalladium (0) in the presence of zinc chloride and a phosphine compound. When M is ZnCl 2, the preferred catalyst is tris (dibenzylideneacetone) dipalladium (0) in the presence of a phosphine compound.

Suitably, the reaction is carried out in an inert aprotic polar coordination solvent such as tetrahydrofuran, diethyl ether, dioxane, 2-dimethoxyethane, acetonitrile, dimethylformamide, dimethylsulfoxide and the like, And is performed in an inert atmosphere. Suitably, the reaction is initially carried out at a low temperature, for example about -78 캜, and the final stage of the reaction is carried out at ambient temperature.

EP 0 444 889, the applicant is Merck Co., and EP 0 430 037, the applicant, Banyu Pharmacetical Co., describes a similar method where M is an organic alkyl tin have.

Compounds of formula (X) are well known in the art and are described in detail in EP 0 444 889 (Merck & Company), EP 0 430 037 (Vannamascaric Company) and Rano et al, Tet. Letters, 1990, 31 , 2853.

Compounds of formula (XI) are well known in the art and can be prepared according to the methods described in Heterocycles, 1992, 33 (2) , 813. The following examples are intended to illustrate the invention rather than to limit the scope of the invention in any way.

General description : The solution was dried using anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. Column chromatography on silica gel using Merck silica gel 60 with a particle size of less than 0.063 mm (0.063 mm).

Example 1

Ethyl-5-methyl-1,2-pyrazol-5-yl) -6 - [(1R) - Hydroxyethyl] carbapen-2-yl) -3-carboxylate

(5R, 6S) -2- (l-ethyl-5-methyl-l, 2-pyrazol-5-yl) -6- [ (200 mg) was added to a solution of ethyl E-2-bromomethylbut-2-enoate (1 mg) in N-methylpyrrolidinone (253 mg) [Reference: F. Ameer et al, J. Chem. Soc., (1983), 2293].

After 2 hours, the solution was diluted with ethyl acetate, washed with water (3x), dried over anhydrous magnesium sulfate and concentrated. The product was purified using Flash silica gel chromatography eluting with 50% ethyl acetate / hexanes followed by ethyl acetate to give a pale yellow foam (153 mg, 58%);

_{(C 22 H 29 N 3 O} 6 Molecular weight analysis of: Found M ⁺ 431.2065; theory M 431.2056); n _max (CH ₂ Cl ₂ ) 3605 (w), 1774, 1712 cm ^-1 ; _{d H (CDCl 3) 1.24-1.41 (} 9H, m), 1.82 (1H, d, J 4.9Hz), 1.98 (3H, d, J 7.3Hz), 2.28 (3H, s), 3.16 (1H, dd, J 2.8, 6.6 Hz), 3.27 (1H, dd, J 9.0, 18.5 Hz), 3.57 (1H, dd, J 9.9,18.5 Hz), 4.07 (2H, q, J 7.3 Hz), 4.17-4.29 m), 5.03 and 5.11 (2H ABq, J 11.9 Hz), 6.94 (1H, s) and 7.21 (1H, q, J 7.3 Hz).

Example 2

Methyl-cyclohexyloxycarbonyloxymethyl (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- 3-carboxylate

(a) iodomethyl 1-methylcyclohexylcarbonate

1-Methylcyclohexanol (4.57 g) in dichloromethane (40 ml) was cooled in a water bath and treated with pyridine (3.24 ml). Chloromethyl chloroformate (3.65 ml) in dichloromethane (10 ml) was added dropwise using a pressure equalizing funnel. The mixture was stirred for 2 hours, then washed with water (2 ×), dried (MgSO ₄₎ and evaporated after that give a red oil which was dissolved in dichloromethane and silica gel (230-400 mesh ASTM) to give chloromethyl 1-methylcyclohexyl carbonate (8.97 g) as a colorless oil (after evaporation): ν _max (CH ₂ Cl ₂ ) 2940, 2865, 1763, 1444, 1346, 1292, and 1237 cm ^-1 ; _{δ (CDCl 3) 1.25-1.70 (11H} , m), 2.12-2.18 (2H, m), 5.69 (2H, s) ppm.

Chloromethyl 1-methylcyclohexylcarbonate (2.07 g) in acetone (7.5 ml) was treated with 2,6-lutidine (0.116 ml). Sodium iodide (2.25 g) was then added and the resulting mixture was stirred for 1.5 hours. Then additional sodium iodide (1.5 g) was added and stirring was continued. After a total of 2.5 hours, the acetone was removed and the layers were separated by the addition of CH ₂ Cl ₂ / water. It washed dichloromethane layer with aqueous Na ₂ S ₂ O ₃ 5%, dried (MgSO ₄₎ and evaporated to give an oil. This was taken up in hexane (50 mL), loaded on a silica gel column and 5% ethyl acetate in hexanes to give the iodomethyl compound, which eluted on the column: δ (CDCl ₃ ) 1.26-1.35 (2H, 1.65 (inclusive at 9H, m, delta 1.52), 2.10-2.20 (2H, m), 5.69 (s) and 5.91 (s) (both 2H, ratio 1: 5) ppm.

(b) 1-Methylcyclohexyloxycarbonyloxymethyl (5R, 6S) -6- [(R) -hydroxyethyl] -2- Carbapen-2-yl) -3-carboxylate

To a solution of (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (1-ethyl (200 mg) was treated with iodomethyl 1-methylcyclohexylcarbonate (363 mg) in tetrahydrofuran (0.5 ml) to give Respectively. The mixture was stirred under argon for 20 min. Ethyl acetate (20 mL) was added and washed with water (3 x 25 mL), followed by 5% Na ₂ S ₂ O ₃ (20 mL), and 0.05 M HCl, then with brine. After drying (MgSO ₄ ), the ethyl acetate was evaporated, CH ₂ Cl ₂ / hexane was loaded and silica gel (230-400 mesh ASTM) (2.5 x 12 cm column) eluting with an ethyl acetate / ≪ / RTI > to obtain a purified rubber. The fractions containing the product were combined, evaporated and chromatographed again on silica gel (230-400 mesh ASTM) (2x) eluting with acetone: hexane (1: 1). The fractions containing the product were combined and evaporated. Hexane was added and the mixture was evaporated to give 1-methylcyclohexyloxycarbonyloxymethyl (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- Carboxylate (187 mg): ν _max (CH ₂ Cl ₂ ) 3678, 3601, 2939, 1773, 1598, 1546, 1450, 1380, 1317, and 1241 cm ^-1 ; _{λ max (EtOH / nm 325 (} ε / dm 3 mol -1 10,924), 213 (ε / dm 3 mol -1 9,391); δ (CDCl 3) 1.2-1.5 (m , including d at 14H, δ1.35 , J 6.4, s at t, J 7.3 Hz and delta 1.51 at delta 1.39), 1.93 (1H, d, J 4.7 Hz), 2.05-2.2 (2H, m), 2.28 (3H, s), 3.18 (1H, dd, J 2.7 6.5 Hz), 3.29 (1H, dd, J 9.1 18.7 Hz), 3.64 4.30 (2H, m), 5.90 (2H, s), 7.05 (1H, s) ppm.

Example 3

(5R, 6S) -2- (1-ethyl-5-methylpyrazol-3-yl) -6 - [(1R) -1-hydroxyethyl ] Carbapen-2-yl) -3-carboxylate

The product prepared in Preparation 1 (200 mg, 0.61 mmol) was dissolved in N-methylpyrrolidin-2-one (2 mL). A solution of 2-methoxyprop-2-ylcarbonyloxymethyl iodide (0.34 g, 1.3 mmol) in N-methylpyrrolidin-2-one (0.5 ml) After 0.5 h the solution was diluted with ethyl acetate (15 mL) and the solution was washed with water (3 x 15 mL), 5% sodium thiosulfate (15 mL), then saturate (15 mL) . The organic extracts were dried (Na ₂ SO ₄ ), concentrated to an oil and purified by chromatography on silica gel eluting with a mixture of acetone / toluene components to give a pale yellow solid which was recrystallized from acetyl / diethyl ether To give the desired compound (0.23 g, 87%) as a colorless oil; (Found: M ⁺ 435.2007, C ₂₁ H ₂₉ N ₃ O ₇ requires M 435.2006); ? _max (CHCl ₃ ) 3612, 3016, 2981, 2937, 1771, 1734 (sh), 1596 cm ^-1 ; _{δ H (CDCl 3) 1.38-1.45 (} 12H, m), 1.81 (1H, d, J4.9Hz), 2.29 (3H, s), 3.18 (1H, dd, J2.8, 6.6Hz), 3.30 (1H (dd, J 9.1, 18.8 Hz), 3.64 (1H, dd, J 9,9, 18.8 Hz), 4.08 (2H, q, J 7.3 Hz), 4.16-4.29 , J 5.5 Hz), 6.03 (1H, J5.5 Hz) and 7.02 (1H, s) ppm.

Recipe 1

(5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapen-

(a) Ethyl 1-ethyl-5-methylpyrazole-3-carboxylate

N-Ethylhydrazine oxalate (12 g) in glacial acetic acid (100 ml) was cooled in a cold bath and treated with ethyl 2,4-dioxovalerate (11.24 ml). After the addition is complete, the mixture is stirred at room temperature; After about 45 minutes, the mixture is warmed to dissolve the insoluble ethyl hydrazine oxalate. The mixture was stirred for an additional 2 hours, then poured into water (about 300 mL) / ethyl acetate (about 700 mL) and the solid K ₂ CO ₃ was carefully added with stirring until the pH was neutral. After separation, the aqueous layer was reextracted with ethyl acetate. The oil and the combined ethyl acetate extracts were dried (MgSO _4), and the solvent was obtained. CH ₂ Cl ₂ / hexanes and chromatography on silica gel eluting with a gradient eluent of ethyl acetate / hexane mixture (2: 8 to 1: 1) to give ethyl 1-ethyl-5-methylpyrazole-3 -Carboxylate (13.2 g); v _max (CH ₂ Cl ₂ ) 1717, 1446, 1389, and 1219 cm ^-1 ; _{δ (CDCl 3) 1.38 (3H} , t, J7.2Hz), 1.42 (3H, t, J7.3Hz), 2.30 (3H, s), 4.17 (2H, q, J7.3Hz), 4.38 (2H, q , J7.1Hz), 6.55 (1H, s); (C 9 H 14 N 2 O ₂ molecular weight analysis of: found m / z 182.1055; Calcd m / z 182.1055).

(b) 1-Ethyl-5-methylpyrazole-3-carboxylate

Treatment of the resulting 1-ethyl-5-methylpyrazole-3-carboxylate (10.93 g) in ethanol (70 ml) with KOH (3.69 g) followed by water (30 ml) Followed by stirring and heating. Ethanol was removed using a rotary evaporator and ethyl acetate / water was added. The pH of the mixture was adjusted to 3.0 to separate the layers. The aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were extracted using an excess of aqueous NaHCO ₃ . After swelling the NaHCO ₃ extract the excess acid, the pH was adjusted to 3, followed by the addition of NaCl to the solution. The mixture was then repeatedly extracted with ethyl acetate and the combined extracts were dried (MgSO ₄ ) and evaporated. The residue was triturated with diethyl ether to give the acid as a solid (5.65 g); ? _max (CH ₂ Cl ₂ ) 2754, 2598, 1698, 1498, 1464, 1387, and 1233 cm ^-1 ; (1H, s) ppm; (C ₇ H ₁₀ N ₂ O (CDCl ₃ ) 1.40 (3H, t, J 7.3 Hz), 2.32 ₂ : found value m / z 154.0740; theoretical value m / z 154.0742).

(c) N-Methoxy-N-methyl-1-ethyl-5-methylpyrazole-3- carboxamide

Ethyl-5-methylpyrazole-3-carboxylic acid (5.25 g) in dry dichloromethane (100 ml) containing N, N-dimethylformamide (0.26 ml) was cooled in a cold bath and dichloromethane Was treated with a solution of oxalyl chloride (3.27 ml) in water (25 ml) and added dropwise. The mixture was stirred at low temperature for 25 minutes and then allowed to warm to room temperature, where gas evolution was observed. After 10 minutes, the solvent was removed by evaporation in vacuo, toluene was added and removed (x2) to check for any residual HCl, and the oxalyl chloride was removed. The resulting acid chloride was redissolved in dry dichloromethane and then treated with N, O-dimethylhydroxyamine hydrochloride (3.61 g). The mixture was cooled in a cold bath and treated with pyridine (6.0 mL). The mixture was then stirred at room temperature for 1.5 hours, then diluted with ether (100 mL) and washed with water. The organic layer was then dried (MgSO ₄ ) and evaporated to give an oil. This was loaded in dichloromethane and chromatographed on silica gel eluting with an ethyl acetate / hexane mixture to give hydroxamate (5.2 g) as a solid after evaporation of the required fractions; ? _max (CH ₂ Cl ₂ ) 2982, 2937, 1641, 1489, 1445, 1379, and 975 cm ^-1 ; _{δ (CDCl 3) 1.43 (3H} , t, J7.3Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s), 4.13 (2H, q, J7.3Hz), 6.49 ( 1H, s); (Molecular weight analysis for C ₉ H ₁₅ N ₃ O ₂ : found m / z 197.1164; theory m / z 197.1164).

(d) 3-acetyl-1-ethyl-5-methylpyrazole

Methoxy-N-methyl-1-ethyl-5-methylpyrazole-3-carboxamide (3.12 g) in dry tetrahydrofuran (60 ml) was cooled in a cold bath and 3.0 M < / RTI > solution of methylmagnesium bromide. After stirring for 1.5 h, the mixture was poured into a mixture of methanol (100 mL) and 5 M aqueous HCl (10 mL) in a cold bath. The mixture was then evaporated to reduce its volume and treated with a mixture of dichloromethane, water and saturated water. The combined dichloromethane extracts were dried (MgSO ₄ ) and evaporated to give an oil (2.26 g) which solidified upon standing; v _max (CH ₂ Cl ₂ ) 1680, 1446, 1425, 1380, 1324, 1208, and 945 cm ^-1 ; _{δ (CDCl 3) 1.44 (3H} , t, J7.3Hz), 2.30 (3H, s), 2.53 (3H, s), 4.13 (2H, q, J7.3Hz), 6.51 (1H, s); (Molecular weight analysis for C ₈ H ₁₂ N ₂ O: found m / z 152.0949; theory for m / z 152.090).

(e) Synthesis of (3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] -3- [ Azetidin-2-one

Acetyl-1-ethyl-5-methylpyrazole (3.51 g) in dry tetrahydrofuran (THF) (150 ml) was cooled in an acetone / solid carbon dioxide bath and then treated with 1M of lithium bis (trimethylsilyl ) Amide solution (50 ml). The mixture was stirred for 45 min and then (6R, 4R) -4-acetoxy-3 - [(1R) -1- tert- butyldimethylsilyloxyethyl] azetidinone (6.6 g) Lt; / RTI > The mixture was stirred at low temperature for 3.5 hours. Then a saturated aqueous ammonium chloride, then ethyl acetate was added and the mixture was allowed to warm to room temperature. A small amount of water was added to separate the layers, and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extracts were washed with a saturated solution and evaporated to dryness. Chromatography on silica gel eluting with ethyl acetate / hexane mixture gave the desired compound (3.65 g); v _max (CH ₂ Cl ₂ ) 3411, 1761, 1678, 1376, 1151, and 838 cm ^-1 ; _{δ (CDCl 3) 0.064 (6H} , s), 0.86 (9H, s), 1.20 (3H, d, J6.3Hz), 1.44 (3H, t, J7.3Hz), 2.31 (3H, s), 2.89 ( (1H, dd, J1.8 4.9 Hz), 3.15 (1H, dd, J10.0 Hz, 17.1 Hz), 3.50 (1H, dd, J3.5 17.0 Hz), 4.06-4.25 s), 6.53 (1 H, s); (Molecular weight analysis for C ₁₉ H ₃₃ N ₃ O ₃ Si: found m / z 379.2296; theory m / z 379.2291).

(f) Preparation of allyl (2R and 2S) -2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] Tert-butyldimethylsilyloxyethyl] -2-oxoazetidinyl} -2-hydroxyacetate.

(3S, 4R) -4 - [(1-Ethyl-5-methylpyrazol-3-yl) carbonyl < / RTI > Methyl] -3 - [(R) -1,3-tert-butyldimethylsilyloxyethyl] azetidin-2-one (3.6 g) and allyl glyoxylate hydroxide (1.66 g) were heated under reflux. Through the Tlc of the reaction mixture, it can be seen that the reaction is proceeding to near completion, and for this reason more allyl glyoxylate hydroxide (190 mg) was added and the mixture was heated with reflux for an additional 45 minutes. The mixture was cooled and toluene was removed to obtain the crude allyl (2R and 2S) -2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] 3 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-oxoazetidinyl} -2-hydroxyacetate, which was used in the next step; ? _max (CH ₂ Cl ₂ ) 3681, 3518, 1758, 1676, 1448, 1376, 1326, 1209, 1148, 1092, 954, and 836 cm ^-1 ; δ (CDCl ₃₎ inter alia 0.035 (s), 0.061 (s ) ( together 6H), 0.858 (s), 0.865 (s) ( together 9H), 1.21 (d, J6.2Hz ), 1.24 (d, J6. (2H, m), 6.53 (s), 6.56 (s, 3H), 1.44 (3H, t, J 7.2 Hz), 2.31 (3H, s), 2.95-3.00 s) ppm.

(g) Synthesis of allyl 2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] -3- [ Silyloxyethyl] -2-oxoazetidinyl} -2- (tri-n-butylphosphoranylidene) acetate.

To a solution of allyl (2R and 2S) -2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] -3- (R) -1,3-tert-butyldimethylsilyloxyethyl] -2-oxoazetidinyl} -2-hydroxyacetate (raw material obtained from the above production process) was cooled to -20 ° C, 2,6- Was treated with lutidine (1.98 ml) followed by thionyl chloride (1.24 ml). The mixture was stirred for 30 min at -20 < 0 > C, then warmed to room temperature, filtered and the residue was washed with THF (20 mL). The filtrate was evaporated in vacuo, toluene (70 ml) was added, removed in vacuo, and the residual oil was dried in vacuo. The oil was then taken up in 1,4-dioxane (40 ml) under an argon atmosphere and treated with tri-n-butylphosphine (3.11 ml). The mixture was heated for 1 hour. Then, 2,6-lutidine (1.59 ml) was added and the resulting mixture was stirred for an additional 30 minutes. The mixture was diluted with ethyl acetate and water, then washed with a function, and dried (MgSO _4). After removal of the ethyl acetate, the crude product was chromatographed on silica gel eluting with an ethyl acetate / hexane mixture to give the phosphorane, which was used in the next step.

(h) Synthesis of allyl 2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] -3- [ 2-oxoazetidinyl} -2- (tri-n-butylphosphoranylidene) acetate.

The above prepared phosphorane was taken up in 1,4-dioxane (60 ml) and treated with 5M HCl (20 ml). After 1 hour, the mixture was treated carefully pH is slightly until the alkalinity of saturated aqueous of about 40㎖ NaHCO _3, followed by careful of solid NaHCO _3. Saturated function was added and the resulting mixture was extracted twice with ethyl acetate. Dry the combined extracts (MgSO _4), and evaporated. The residue was chromatographed on silica gel eluting with an ethyl acetate / hexane mixture to give the hydroxy compound (2.60 g); ? _max (CH ₂ Cl ₂ ) 3454, 1741, 1667, 1606, 1448, 1403, 1379, 1155, 1087, 953, and 811 cm ^-1 .

(i) Synthesis of allyl (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- Carboxylate.

To a solution of allyl 2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3- yl) carbonylmethyl] -3- [ (2.6 g) was heated under reflux in an argon atmosphere for 4 hours to give 64 (R) -1-hydroxyethyl] -2-oxoazetidinyl} -2- After standing for a further hour, the mixture was heated with reflux for an additional 2 hours. The mixture was cooled and then filtered through a silica gel (particle size 0.040-100 mesh) eluting with ethyl acetate / hexane mixture (1: 1, 6: 4, 7: 3, 8: 0.063 mm) (4.5 x 12 cm). Thus, carbapenem (436 mg) was obtained; ? _max (CH ₂ Cl ₂ ) 3604, 2976, 1774, 1716, 1600, 1546, 1311, 1189 cm ^-1 ; _{λ max (EtOH) /nm321.5 (ε} / dm 3 mol -1 cm -1 14,856, δ (CDCl 3) 1.36 (d, J6.3Hz), 1.39 (t, J7.3Hz) ( together 5H), 1.80 (1H, d, J5.0 Hz), 2.28 (3H, s), 3.19 (1H, dd J2.7 6.7 Hz), 3.28 (1H, dd, J9.0 18.6 Hz), 3.60 M, about d, J 12 Hz), 5.46 (m, 1H), 4.08 (4H, q, J 7.3 Hz), 4.16-4.30 (2H, m), 4.68-4.90 close to d, J17Hz), 5.93-6.08 (1H , m), 7.00 (1H, s) ppm; C 18 H 23 N 3 O 4 molecular weight analysis of: found m / z 345.1693; Calcd m / z 345.1689).

(j) (5R, 6S) -6- [(R) -1-Hydroxyethyl] -2- Sodium carboxylate.

To a solution of allyl (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol- (267 mg) was treated with 2-ethylhexanoate (183 mg) followed by triphenylphosphine (24 mg) followed by tetrakis (triphenylphosphine) palladium (0) (35 mg) under argon and the resulting mixture was stirred for 45 minutes. Then, diethyl ether (100 ml) was added and after stirring for 90 minutes, the mixture was centrifuged. The residual solids were dried in a stream of argon and then in a drier. The solid was then taken up in water containing sodium chloride and chromatographed on DIAION HP20SS resin eluted with water followed by a water / THF mixture (1%, 2%, and 3% THF). The fractions were monitored by HPLC and the fractions containing the product were combined, reduced in volume and lyophilized to give (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- Ethyl-5-methylpyrazol-3-yl) carbapen-2-yl) -3-carboxylate; ? _max (KBr) 1761, 1608, 1577, 1381, 1225 cm ^-1 ; _{λ max (H 2 O) /} nm298 (ε / dm 3 mol -1 cm -1 8,531), δ (D 2 O) 1.26 (d, J6Hz), 1.27 (d, J7Hz) ( together 5H), 2.23 (3H , s), 3.17 (2H, d, J9 Hz), 3.44 (1H, dd, J2.9 6.0 Hz), 4.04 (2H, q, J 7.3 Hz), 4.15-4.25 , s) ppm.

Claims (10)

The compound of formula (I) (I) In this formula, R is Is: R ^? Is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl; R ^{< beta >} is hydrogen, substituted or unsubstituted ( _C1-6 ) alkyl or substituted or unsubstituted aryl; R ^α and R ^β is optionally substituted with or without an additional heteroatom, or to form an unsubstituted 5 or 6 membered heterocyclic ring together; R ¹ is fluorine, a hydroxy group that is not protected or protected by an easily removable hydroxy protecting group, or a (C _1-6 ) alkyl (C _1-6 ) alkyl group that is unsubstituted or substituted by an amino group that is not protected or protected by an easily removable amino protecting group ego; R ² is hydrogen or methyl; R ³ is selected from the group consisting of a group of the formula (a) and a group of the formula (b); (A) (B) CH (R ^a ) O CO R ^b In the above formulas (a) and (b), R ₁ is hydrogen or (C _1-6 ) alkyl, R ₂ is hydrogen, (C _1-6 ) alkyl, (C _1-6 ) alkenyl, (C _1-6 ) alkoxycarbonyl, aryl, or heteroaryl, optionally substituted with halogen, R ₃ is hydrogen, (C _1-6 ) alkyl, or (C _1-6 ) alkoxycarbonyl, R < ₄ > is a pharmaceutically acceptable ester forming group, R ^a is hydrogen, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, methyl, or phenyl, R ^b is (C _1-6 ) alkyl (C _3-7 ) cycloalkyloxy or (C _1-6 ) alkoxy (C _1-6 ) alkyl. Ethyl-5-methyl-1,2-pyrazol-5-yl) -6 - [(1R) - 1-hydroxyethyl] carbapen-2-yl] -3-carboxylate. Methyl-cyclohexyloxycarbonyloxymethyl (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- Pyran-2-yl) -3-carboxylate. (5R, 6S) -2- (1-ethyl-5-methylpyrazol-3-yl) -6 - [(1R) -1-hydroxyethyl ] Carbapen-2-yl) -3-carboxylate. A pharmaceutical composition comprising an antimicrobial compound according to any one of claims 1 to 4 together with a pharmaceutically acceptable carrier or excipient. A method of treating bacterial infections in humans and animals comprising administering a therapeutically effective amount of an antimicrobial compound according to any one of claims 1 to 4. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of bacterial infections. Process for preparing a compound of formula (I) according to claim 1, comprising treating a corresponding compound of formula (I) wherein R is an alkali metal cation with a compound of formula (i) or (ii) (I) (Ii) XCH (R < ^a & gt ^; ) OCOR ^b In the above formula, X is a leaving group. Treating the compound of formula (II) with carbapenem ring forming conditions, and thereafter removing all protecting group (s) if necessary; Converting a first group R ¹ comprising a hydroxyl substituent in the group R ¹ of the added amino or fluorine containing group; Converting the product to a salt; (I) according to claim 1, comprising all or any step of esterifying the product. (II) In this formula, R, R < ¹ > and R < ² > are as defined above, R ³ is a readily removable carboxy protecting group, X is oxygen or the group PR ⁴ R ⁵ R ⁶ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are each a substituted or unsubstituted (C _1-6 ) alkyl or a substituted or unsubstituted aryl group. (XI) with a compound of formula (XI) in a cross-linking reaction in the presence of a crosslinking reaction catalyst selected according to M, and if necessary removing any protecting groups and / (I) according to claim 1, comprising the step of converting the compound of formula (X) (XI) M-R In this formula, R ¹ and R ² are as defined above, R ³ is a readily removable carboxy protecting group, X ¹ is a leaving group; M is a metallo group, R is as defined above.